Research Insights

Proteoglycans harboring heparan sulfate (HS) chains are widely found on cell surfaces and in extracellular matrices where they interact with growth factors, receptors, morphogens, and extracellular matrix components and play critical roles in processes such as cell survival, division, migration, differentiation, pathogen binding, and cancer development. HS biosynthesis is a complex process involving initial formation of a linker glycan on proteoglycan core proteins, priming and extension of the HS chains’ polymer backbone, facilitated by the EXT1-EXT2 heterodimeric co-polymerase complex. Homozygous defects in either of these proteins cause embryonic lethality, and heterozygous loss of function has clinical ramifications, including benign tumors. We recently solved the structure of the human EXT1- 2 heterodimeric co-polymerase in complex, providing insights into HS chain synthesis. EXT1 and EXT2 form an obligate heterocomplex of the two homologous proteins. Each protein contains two separate predicted catalytic domains, yet only one of the two domains is active in each protein suggesting that the monomers share catalytic functions. We also discovered an interaction between EXT1-2 and the HS priming enzyme EXTL3. These studies raise important new questions about HS synthesis in vivo and the nature and pathology of HME mutations. This research will advance our understanding of HS biology and its roles in health and disease. Unraveling the mechanisms governing HS backbone synthesis will shed light on the molecular basis of HS-mediated cellular processes and pave the way for future development of targeted interventions.

Funder: National Institutes of Health 

Amount: $1,331,828 

PI: Kelley Moremen, Franklin College of Arts and Sciences, Department of Biochemistry and Molecular Biology